Cyclin-dependent kinase inhibitors (CDKIs) have been shown to block human immunodeficiency virus (HIV) and herpes simplex virus. For example, the CDKI flavopiridol (Flavo) also has been shown to be a very potent anti-HIV compound (Chao, et al., J. Biol. Chem. 275:28345-28348, 2000). It has more recently been shown that three CDKIs, Flavo, purvalanol A (Purv), and methoxy-roscovitine (M-Ros), block Moloney murine leukemia virus (MLV) transcription events. Using gene expression microarray technology to further examine the inhibitory effects of CDKIs on MLV, several genes were identified that were down-regulated in 3T3 cells by CDKI treatment. These genes included the pre B-cell leukemia transcription factor 1 (Pbx1) and HMG I family members, e.g., HMG I-C (see, e.g., Chao et al., Mol. Cell. Biol. 23:831-841, 2003).
Pbx1 is a member of the TALE (three-amino acid loop extension) class of homeodomain transcription factors, which are components of heteroligomeric protein complexes that regulate gene expression. Pbx1 was first identified due to its involvement in a chromosomal translocation associated with pre-B cell human leukemia in which the E2A gene is truncated and fused to Pbx1 (Kamps et al., Cell 60:547-555, 1990; Nourse et al., Cell 60:535-545, 1990). It has also been implicated in the regulation of pancreatic development and diabetes mellitus (Kim et al., Nature Genet. 30:430-435, 2002). Pbx 1 binds the Pbx Consensus Element (PCE), TGATTGAC, as a heterodimer with other homeodomain factors such as MEIS1 or PREP1 (Chang, et al., Mol. Cell Biol. 17:5679-5687, 1997; Knoepfler & Kamps, Oncogene 14:2521-2531, 1997). In investigating the role of Pbx1 in the control of MLV transcription, PBX-binding regulatory elements were identified in the MLV long terminal repeat through which PBX1 and PREP1 heterodimers bind and positively regulate MLV transcription (see, e.g., Chao et al., Mol. Cell. Biol. 23:831-841, 2003).
High mobility group (HMG) proteins are members of a class of small nonhistone DNA-binding proteins that modulate chromatin structure and function. The HMG I(Y) family consists of three members (see, e.g., Bustin and Reeves, Prog. Nucleic Acids Res. Mol. Biol. 54:35-100, 1996): HMG I and HMG Y are alternatively spliced mRNA that are expressed from the same gene; HMG I-C is closely related, but transcribed from a different gene. It has been shown that HMG I family proteins can be involved in the integration of HIV, MLV, and Avian Sarcoma Virus integration in vitro (see, e.g., Farnet and Bushman Cell 88:483-492, 1997; Hindmarsh et al, J. Virol. 73:2994-3003, 1999;and Li et al. J Virol. 72:2125-2131, 1998). Additionally, it was reported that HMG I/Y modulates binding of transcription factors to the LTR of HIV (Henderson et al., J. Virol. 74:10523-10534, 2000).